Abstract
BACKGROUND
The pivotal NINDS rt-PA trials excluded ischemic stroke patients with specific minor presentations or rapidly improving symptoms. The rt-PA product label notes that its use for minor neurological deficit or rapidly improving stroke symptoms has not been evaluated. As a result, patients with low NIHSS scores are not commonly treated in clinical practice. We sought to further characterize the minor stroke patients that were included in the NINDS trials.
METHODS
Minor strokes were defined as NIHSS ≤ 5 at baseline for this retrospective analysis, as this subgroup is most commonly excluded from treatment in clinical practice and trials. Clinical stroke syndromes were defined based on prespecified NIHSS item score clusters. Clinical outcomes were reviewed generally and within these cluster subgroups.
RESULTS
Only 58 cases had NIHSS scores of ≤0–5 in the NINDS trials (42 rt-PA and 16 placebo), and 2971 patients were excluded from the trials due to “rapidly improving” or “minor symptoms” as the primary reason. No patients were enrolled with isolated motor symptoms, isolated facial droop, isolated ataxia, dysarthria, isolated sensory symptoms, or with only symptoms/signs not captured by the NIHSS score (i.e., NIHSS=0). There were three or fewer patients with each of the other isolated deficits enrolled in the trial.
CONCLUSIONS
The NINDS trials excluded a substantial number of strokes with minor presentations, those that were included were small in number, and conclusions about outcomes based on specific syndromes cannot be drawn. Further prospective, systematic study of this subgroup is needed.
Keywords: Acute stroke, thrombolysis, clinical trials
Background
The pivotal NINDS rt-PA stroke trials established intravenous (IV) rt-PA as a therapy for acute ischemic strokes within three hours of symptom onset. The NINDS trials required exclusion of ischemic stroke patients if they had specific minor or rapidly improving symptoms.1 This led to the rt-PA (alteplase) product label broadly stating that “treatment ... in patients with minor neurological deficit or with rapidly improving symptoms ... has not been evaluated.” In this setting, the role of IV rt-PA for treatment of minor stroke syndromes at acute presentation remains unclear.
The NINDS trials specifically excluded ischemic stroke cases with no measurable deficit on the NIH Stroke Scale (NIHSS) score; rapidly improving deficit, or; symptoms of isolated sensory stroke, isolated ataxia, isolated dysarthria, or isolated facial weakness.2 However, subsequent clinical guidelines have not precisely defined minor strokes or rapid improvement. For example, the American Heart Association stroke guidelines state that eligibility for rt-PA requires that “neurological signs should not be minor and isolated.”3 Epidemiologic studies have used the gross definition of NIHSS score ≤5 for “mild” stroke.4, 5 Most recent stroke clinical trials exclude NIHSS scores of less than 5 or 6 from enrollment on the presumption that this represents the minor subgroup.6–9 A definition of NIHSS ≤ 5 for minor stroke would include all strokes explicitly excluded from the NINDS trials, and 58 of the cases enrolled in the trials.
Currently, a substantial proportion (20%–46%) of patients who present to emergency departments, and are otherwise eligible for thrombolysis, are not treated, primarily because their symptoms are perceived to be minor or rapidly improving.4, 10–15 Furthermore, over half of all ischemic strokes in the United States have a NIHSS score ≤5.5,16
Recent data suggest that untreated patients with ischemic stroke perceived as minor (at presentation, or due to improvement prior to the treatment decision) have substantial rates of disability. Disability or death at hospital discharge, as measured by modified Rankin Score (mRS) 2–6 or not discharged home, has been reported in the range of 25%–64%. 11,17–19 Disability or death at 90 days, as measured by mRS 2–6, has been reported in the range of 32–58%. 19,20 This disability may be due to unmeasured cognitive effects of the stroke, extension of the stroke after acute presentation, or new events resulting from related co-morbidities, or it may be a direct result of the acutely presenting deficit. In some cases, it may be due to disability predating the incident stroke.
We sought to further characterize the minor stroke patient group with the lowest NIHSS scores (NIHSS≤5) that were included in The NINDS rt-PA Stroke Study. We reviewed their rate of inclusion in the trial, clinical presentations, and clinical outcomes in detail. This analysis was undertaken to explore the effectiveness of IV rt-PA treatment for this subgroup of stroke patients based on this pivotal study, and to consider the need for further randomized studies.
Methods
The NINDS rt-PA Stroke Study consisted of two randomized trials that tested the safety and efficacy of 0.9 mg/kg IV rt-PA for acute ischemic stroke within three hours of symptom onset.1 Patients were excluded from the trials if they had “rapidly improving or minor symptoms.” The NINDS trialists reported the explicit exclusion of isolated symptoms of sensory loss, facial weakness, ataxia, or dysarthria, no measurable deficit on the NIHSS (i.e., NIHSS=0), or a rapidly improving neurological deficit.2
For the purposes of this retrospective analysis, minor strokes were defined as NIHSS ≤5 at baseline. Clinical stroke syndromes were defined based on prespecified NIHSS item score clusters, as shown in Table 1. We defined individual isolated symptoms or signs by NIHSS score, and considered secondary definitions in which additional concurrent NIHSS item abnormalities were present.
Table 1.
Clinical Stroke Syndromes as Defined by NIHSS Item Clusters
| Clinical Stroke Syndrome | Definition Based on NIHSS Items |
|---|---|
| Aphasia alone | NIHSS item 9>0, 1b and 1c may or may not be >0, and no others > 0 |
| Aphasia PLUS | NIHSS item 9>0, 1b and 1c may or may not be >0, plus at least one other > 0 |
| Single limb severe weakness alone | Only one of the following NIHSS items: 5a, 5b, 6a, or 6b ≥3; and no other limb weakness >0, and no others >0 |
| At least one limb with severe weakness PLUS | NIHSS item 5a, 5b, 6a, or 6b ≥3, plus at least one other >0 |
| Hemimotor alone | NIHSS items 4, 5a, and 6a all >0, and no others >0 OR 4, 5b, and 6b all >0, and no others >0 |
| Hemimotor PLUS | NIHSS items: 4, 5a, and 6a, all >0 but not 5b or 6b, plus others >0 OR 4, 5b, and 6b all >0, but not 5a or 6a, plus at least one other >0 |
| *Hemisensory alone | NIHSS item 8 >0, plus no others >0 |
| Hemisensory PLUS | NIHSS item 8 >0 with at least one other >0 |
| ACA (leg weakness) only | NIHSS item 6a or 6b >0, but not both 6a and 6b, and no others >0 |
| ACA (leg weakness) PLUS | NIHSS item 6a or 6b >0, but not both 6a and 6b, and not 4 or 5, plus at least one other > 0 |
| Cortical alone | NIHSS item 9 and/or 11 >0, and no other > 0 |
| Cortical PLUS | NIHSS item 9 and/or 11 >0, plus at least one other >0 |
| *Limb ataxia alone | NIHSS item 7 >0, and no other > 0 |
| Limb ataxia PLUS | NIHSS item 7 >0, plus at least one other >0 |
| Vision loss alone (NIHSS item 3 >0, and no other > 0) | NIHSS item 3 >0, and no other > 0 |
| Vision loss PLUS | NIHSS item 3 >0, plus at least one other >0 |
| *Facial droop alone | NIHSS item 4 >0, and no other > 0 |
| Facial droop PLUS | NIHSS item 4 >0, plus at least one other >0 |
| *Dysarthria alone | NIHSS item 10 >0, and no other > 0 |
| Dysarthria PLUS | NIHSS item:10 >0, plus at least one other > 0 |
| *NIHSS = 0 | May include isolated vertigo, truncal ataxia |
Explicitly excluded in the NINDS trials
NIHSS items: 1a: level of consciousness (LOC); 1b: LOC questions of month and age; 1c: LOC commands of eyes and grip; 2: best gaze; 3: visual fields; 4: facial palsy; 5a: left arm; 5b: right arm; 6a: left leg; 6b: right leg; 7: limb ataxia; 8: sensory; 9: best language; 10: dysarthria; 11: extinction
Clinical outcomes were reviewed generally and within these cluster subgroups. A favorable outcome was defined as a mRS of 0 or 1 at 90 days. Post-stroke intracranial hemorrhages were reviewed in each subgroup. We also investigated potential stroke extension or recurrent events, as indexed by an increase in NIHSS score to >5 from baseline to 90 days or, and at least a two-point worsening in NIHSS from baseline to 2 hours and baseline to 24 hours.
Results
Over the four years of the trial, 17,324 patients were excluded; according to screening logs, 52% of these were excluded due to time of presentation. Of the remaining 8,315, the “primary reason” for exclusion was minor symptoms for 1,039 and rapid improvement for 1,732. Among 624 patients enrolled in the trials, 58 cases had NIHSS scores ≤ 5, of which 42 were in the rt-PA group and 16 were in the placebo group. 21,22
Table 2 shows characteristics of the minor stroke group (age, sex, history of diabetes mellitus, hyperlipidemia, or hypertension, atrial fibrillation, presumed etiology, stroke etiology after diagnostic testing, and time to treatment) compared with the rest of cases enrolled in the study. Subjects with minor strokes were younger and more often had small-vessel etiologies than those with more severe strokes.
Table 2.
Characteristics of Minor Stroke Group Compared to All Others Enrolled in the NINDS rt-PA Study
| Characteristics | Minor Strokes (NIHSS 0–5) | All Others (NIHSS>5) | p-value* |
|---|---|---|---|
| Age (mean and s.d.) | 66.2 (12.0) | 67.0 (11.6) | p=0.02 |
| Sex (% male) | 42 (72.4%) | 320 (56.5%) | NS |
| H/O Hypertension | 37 (63.8%) | 371 (65.6%) | NS |
| H/O Diabetes Mellitus | 14 (24.1%) | 117 (20.7%) | NS |
| H/O Hyperlipidemia | 17 (29.3%) | 124 (21.9%) | NS |
| Atrial Fibrillation | 9 (15.5%) | 106 (18.7%) | NS |
| Baseline NIHSS Score (median and range) | 4 (4) | 15.5 (31) | -- |
| Presumed Etiology | p<0.0001 | ||
| -Small Vessel | 28 (48.3%) | 53 (9.4%) | |
| -Large Vessel | 14 (24.1%) | 238 (42.1%) | |
| -Cardioembolic | 15 (25.9%) | 258 (45.6%) | |
| -Other | 1 (1.7%) | 17 (3.0%) | |
| Proportion Treated at 0–90 Minutes from Onset | 22 (37.9%) | 280 (49.5%) | p=0.09 |
| Etiology Assigned after Diagnostic Testing | P<0.0001 | ||
| -Small Vessel | 17 (29.3%) | 44 (7.8%) | |
| -Large Vessel | 8 (13.8%) | 122 (21.6%) | |
| -Cardioembolic | 17 (29.3%) | 224 (39.6%) | |
| -Other | 4 (6.9%) | 18 (3.2%) | |
| -Unknown | 12 (20.7%) | 158 (27.9%) | |
NS is listed if p≥0.10
Table 3 shows the number of patients within each NIHSS symptom cluster; this categorization allows for the same patient to be in more than one cluster. Among the 58 cases that were enrolled, only two had isolated aphasias, and only three had isolated vision loss. No patients were enrolled with isolated motor symptoms, isolated severe limb weakness, isolated facial droop, isolated ataxia, dysarthria, isolated sensory symptoms, or isolated with only symptoms/signs not captured by the NIHSS score (i.e., NIHSS=0).
Table 3.
Three-Month Clinical Outcome among Minor Ischemic Strokes (NIHSS <=5), based on Clusters of NIHSS Items with Abnormalities at Presentation
| Treatment Arm | rt-PA (n=42) | Placebo (n=16) | ||||
|---|---|---|---|---|---|---|
| Cluster category* | N | mRS 0-1 | NIHSS<=5 | n | mRS 0-1 | NIHSS<=5 |
| Aphasia alone | 1 | 0 | 1 | 1 | 1 | 1 |
| Aphasia PLUS | 8 | 7 | 8 | 3 | 1 | 1 |
| Single limb severe weakness alone | 1 | 0 | 0 | 0 | NA | NA |
| At least one limb with severe weakness PLUS | 1 | 1 | 1 | 0 | NA | NA |
| Hemimotor alone | 0 | NA | NA | 0 | NA | NA |
| Hemimotor PLUS | 10 | 9 | 7 | 4 | 3 | 2 |
| Hemisensory PLUS | 15 | 15 | 11 | 5 | 5 | 3 |
| ACA (leg weakness) only | 1 | 0 | 0 | 0 | NA | NA |
| ACA (leg weakness) PLUS | 1 | 0 | 1 | 0 | NA | NA |
| Cortical alone | 0 | NA | NA | 0 | NA | NA |
| Cortical PLUS | 12 | 9 | 10 | 5 | 3 | 3 |
| Limb ataxia PLUS | 3 | 2 | 2 | 2 | 2 | 2 |
| Vision loss alone | 1 | 1 | 1 | 2 | 2 | 1 |
| Vision loss PLUS | 2 | 1 | 0 | 0 | NA | |
| Facial droop PLUS | 34 | 28 | 24 | 9 | 6 | 4 |
| Dysarthria PLUS | 26 | 21 | 18 | 10 | 7 | 5 |
Note: No patients were seen with symptoms/signs that explicitly required exclusion from the NINDS trials, including isolated sensory symptoms, dysarthria, ataxia, facial weakness, or NIHSS=0.
Table 4 shows overall distribution of 90-day mRS scores in rt-PA and placebo groups. Minimal or no disability (mRS 0 or 1) was seen in 33/42 (78.6%; 95% C.I. 63.2–89.7%) of rt-PA cases and 13/16 (81.3%; 95% CI 54.4%–96.0%) of the placebo cases. No treatment effect (OR 0.85; 95% CI: 0.20–3.63) was demonstrated when comparing favorable outcomes between the two arms of the trial in this underpowered (Beta<25%) post-hoc analysis. It should be noted that four of the 58 minor strokes had baseline disability (mRS≥2), and all were in the rt-PA group. There was one symptomatic intracranial hemorrhage (2.4%) in the rtPA arm in a subject with baseline NIHSS 3 due to isolated left leg weakness. There was one symptomatic intracranial hemorrhage (2.4%) in the IV rtPA arm; this subject had a baseline NIHSS score of 3 due to isolated left leg weakness and subsequently died. There were no symptomatic hemorrhages in the placebo group, and there were no asymptomatic intracranial hemorrhages in either group. Neurological worsening was numerically, but nonsignificantly, less frequent in rt-PA versus placebo arms based on NIHSS>5 at 90 days (6.3% vs 9.5%; see subgroups in Table 3), two-point worsening at 2 hours (4.8% vs. 18.8%), and two-point worsening at 24 hours (11.9 vs 25%).
Discussion
Among the 624 patients in the NINDS trial, only 58 (9.3%) had NIHSS scores of ≤5. Consistent with the NINDS trialists’ description of the explicit exclusions, no patients with isolated ataxia, dysarthria, facial weakness, sensory symptoms, or isolated symptoms/signs not captured by the NIHSS score (i.e., NIHSS=0) were enrolled. However, there were only three or fewer patients enrolled with each of the isolated deficits that were not explicit exclusions in the NINDS trials.
The contrast between the proportion of minor strokes in the NINDS trials (9%) and recent epidemiologic data that suggest that minor strokes (NIHSS <6) comprise between 20%–46% of strokes that arrive within three hours to hospital emergency departments seems greater than can be readily explained by the explicit exclusions of the NINDS trials. Furthermore, our analysis of clinical syndromes enrolled in the NINDS trials suggests that many key syndromes were not well represented. Some syndromes were not included in the trial due to the explicit requirement of their exclusion, but others seen in the emergency setting (pure motor hemiparesis, isolated aphasias, isolated homonymous hemianopsia) were not included in any significant number despite no explicit exclusion from the trial.
The relative absence of minor strokes in the NINDS trials may be due, in part, to factors specific to the era of the trials (early 1990s). Emergency physicians and triage nurses may not have recognized these presentations as strokes, as the trial took place prior to any proven therapy for stroke that would warrant routine acute evaluations. It is also possible that there has been a shift in the proportion of patients with minor symptoms presenting early to emergency departments, either due to changing characteristics of the disease over time, or to increased public awareness to present to medical care emergently.
Perhaps most significantly, while only 58 patients with minor symptoms were enrolled, 2,971 patients were excluded due to “rapidly improving” or “minor symptoms” as the primary reason.21 There may have been a perception among at least some of the NINDS trial investigators that these syndromes were unlikely to be disabling, leading to their exclusion from the trial. This conservative approach would have been reasonable at the time, given rt-PA’s novelty as a stroke therapy and the lack of definitive data on its benefit and safety. The current literature suggests that minor strokes are often associated with substantial disability, but the natural history of minor ischemic stroke based on specific clinical syndromes is still not known.
It has been previously reported that there were no treatment by stroke severity interactions in the NINDS trials, which suggests that minor stroke patients whose symptoms match those enrolled in the NINDS Study should be treated with lytic therapy.22 Of note, however, our retrospective analysis of minor stroke clinical syndromes suggest this subgroup in the NINDS Study is not fully generalizable to the broader minor stroke patient group who may be encountered acutely, both because of explicit exclusions and possible implicit exclusions.
The minor strokes in the NINDS trial in this analysis, defined by NIHSS ≤5, that were included did surprisingly well compared to the proportions of favorable outcomes among minor stroke subgroups recently reported.22 In addition to the possibility that the minor stroke patients enrolled in the trial are not representative of patients now arriving in emergency departments with minor symptoms, it should be kept in mind that the small number of patients in this subgroup leads to wide 95% confidence intervals for the rate of favorable outcome.
It should also be noted that the NINDS rt-PA study investigators have previously explored five minor stroke definitions that are different from that examined in this analysis.2 Definition A required 0 or 1 scores on every baseline pre-treatment NIHSS score item except level of consciousness, Definition B consisted of all presumed small-vessel occlusive patients, Definition C consisted of only motor deficits (including dysarthria and/or ataxia) with or without sensory deficits, Definition D required the lowest quartile of stroke severity in the NINDS trial (NIHSS<10) and no cortical or level of consciousness symptoms, and Definition E required only the lowest quartile of stroke severity in the NINDS trial (NIHSS<10). This exploratory analysis showed favorable treatment effects of rt-PA across all of these definitions. However, because these definitions all included patients with NIHSS>5, they cannot be readily applied to the subgroup of interest in this analysis.
In clinical practice at this time, a large number of patients with minor stroke symptoms as defined by an NIHSS<5 are not treated with thrombolysis. For example, in the American Heart Association Get With the Guidelines Registry from 2003–2009, among 73,044 cases arriving to emergency departments within two hours and not treated with rt-PA, 29,612(41%) were not treated due to mild or improving symptoms, and 75% of these had a baseline NIHSS<5.15 Leading stroke centers vary in their approach to acute treatment of patients with minor symptoms. Many do not treat minor symptoms unless the evaluating stroke physician perceives the symptoms at presentation to be disabling for individual circumstances. Others treat minor syndromes that have proximal arterial occlusions on intracranial vascular imaging, as these are the most likely to have poor outcomes.23,24 Still others treat most minor syndromes, with the rationale that risk is likely to be low, and that even small-vessel events have significant disability rates and are likely to benefit from thrombolytic treatment.1,2 The appropriate approach to strokes with low NIHSS scores is debatable.
In summary, this exploratory analysis suggests that the NINDS trials excluded a substantial number of strokes with minor presentations, those minor stroke syndromes that were included were small in number, and conclusions about outcomes based on specific clinical syndromes cannot be drawn. Further study of this subgroup is needed in larger datasets that have systematically and prospectively included minor strokes. Whether thrombolysis is of benefit to this subgroup of patients excluded from the NINDS Study is uncertain.
Figure 1.
Distribution of mRS Scores at 90 Days among rt-PA and Placebo Groups
Acknowledgments
This research was funded by the National Institutes of Health-National Institute of Neurological Disorders and Stroke (NIH-NINDS K23NS059843) for PK.
Footnotes
CONFLICTS OF INTEREST/DISCLOSURES:
PK: Executive Committee of NIH-funded IMS III trial, which received drug from Genentech, Inc.
JLS: Dr. Saver is a scientific consultant regarding trial design and conduct to CoAxia, Concentric Medical, Talecris, Ferrer, BrainsGate, PhotoThera, and Sygnis (all modest); has received lecture honoraria from Ferrer (modest); has declined consulting/honoraria monies from Genentech since 2002; is a site investigator in the NIH MR RESCUE, CLEAR-ER, and IMS 3 multicenter clinical trials, for which the UC Regents receive payments based on the clinical trial contracts for the number of subjects enrolled; has served as an unpaid site investigator in a multicenter trial run by Lundbeck, and for which the UC Regents received payments based on the clinical trial contracts for the number of subjects enrolled; is a site investigator in a multicenter registry run by Concentric, all for which the UC (University of California) Regents receives payments based on the clinical trial contracts for the number of subjects enrolled; administers stroke thrombolytic therapy in his practice (<5% of effort); is an employee of the University of California, which holds a patent on retriever devices for stroke; and is funded by NIH-NINDS Awards (P50 NS044378 and U01 NS 44364).
SL: Supported in part from NIH grants (1R0 1 HL096944 and 1R0 1 NS052417); Associate Editor of MEDLINK; Independent Medical/Safety Monitor for IMS 3, FAST-MAG, CLEAR-ER, INSTINCT; Acute Advisory Board, National Stroke Association.
DOK: Speaker's bureau of Genentech; National Advisory Board of Boehringer Ingelheim.
YYP: Supported in part by NIH grants (U01 NS054630-04 for ALIAS and IMS III Trials, U01 NS059041 for NETT Network Statistical and Data Management Center, R01 NS062778 for POINT Trial, R01 NS062835 for PRoTECT Trial, and U01 NS061861 for ATACH II Trial); DMC member for IMPACT (Brainsgate).
ECJ: Supported in part by NIH grants (U01 NS054630-04 for ALIAS Trials U01, NS059041 for NETT Network Statistical and Data Management Center, and U 01 NS052220 for IMS III Trial)
JPB: Principal Investigator of NINDS-funded IMS III Trial, UC (University of Cincinnati) SPOTRIAS Center (includes NINDS-funded CLEARER and STOP-IT Clinical Trials), NINDS-funded Familial Intracranial Aneurysm (FIA) Study, and NINDS-funded T-32 Cerebrovascular Fellowship Training Program for Cerebrovascular Disease. Co-investigator of NINDS-funded Genetic and Environmental Risk Factors for Hemorrhagic Stroke, NINDS-funded “Comparison of Hemorrhagic and Ischemic Strokes Among Blacks and Whites,” and NINDS-funded IRIS Trial, CREST, COSS, and SWISS Studies. Genentech Inc. (Supplier of alteplase for NINDS-funded CLEARER, IMS III trials) supplies IA rtPA, EKOS Corporation supplies catheter devices, Concentric Inc. supplies devices, and Johnson and Johnson supplies catheters for the ongoing IMS III Study. Schering Plough supplies drug for NINDS-funded CLEARER Trial. Boehringer Ingelheim has provided honoraria for speaking fees (honorarium last received on 2/15/08). Consulting fees and honoraria are placed in an educational/research stroke fund in the Department of Neurology.
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